CN116370609A - Solid composition comprising a vasoactive intestinal peptide and an absorption enhancer - Google Patents
Solid composition comprising a vasoactive intestinal peptide and an absorption enhancer Download PDFInfo
- Publication number
- CN116370609A CN116370609A CN202310635587.2A CN202310635587A CN116370609A CN 116370609 A CN116370609 A CN 116370609A CN 202310635587 A CN202310635587 A CN 202310635587A CN 116370609 A CN116370609 A CN 116370609A
- Authority
- CN
- China
- Prior art keywords
- vasoactive intestinal
- intestinal peptide
- absorption enhancer
- solid composition
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 title claims abstract description 35
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 title claims abstract description 24
- 102000055135 Vasoactive Intestinal Peptide Human genes 0.000 title claims abstract description 23
- 239000008247 solid mixture Substances 0.000 title claims abstract description 21
- 238000010521 absorption reaction Methods 0.000 title claims abstract description 19
- 239000003623 enhancer Substances 0.000 title claims abstract description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 14
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 14
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 14
- 239000008101 lactose Substances 0.000 claims description 14
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 13
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 13
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 9
- 229940069328 povidone Drugs 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 3
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 3
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 3
- 201000001881 impotence Diseases 0.000 claims description 3
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 241000711573 Coronaviridae Species 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 208000004852 Lung Injury Diseases 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 206010069363 Traumatic lung injury Diseases 0.000 claims description 2
- 206010069351 acute lung injury Diseases 0.000 claims description 2
- PASHVRUKOFIRIK-UHFFFAOYSA-L calcium sulfate dihydrate Chemical compound O.O.[Ca+2].[O-]S([O-])(=O)=O PASHVRUKOFIRIK-UHFFFAOYSA-L 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 239000012153 distilled water Substances 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 229960004667 ethyl cellulose Drugs 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229940014259 gelatin Drugs 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 229950005770 hyprolose Drugs 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 231100000515 lung injury Toxicity 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims 2
- 239000007884 disintegrant Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000008119 colloidal silica Substances 0.000 claims 1
- 229960000913 crospovidone Drugs 0.000 claims 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims 1
- 229940032147 starch Drugs 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 239000012752 auxiliary agent Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 abstract description 3
- 239000008187 granular material Substances 0.000 description 14
- 239000002775 capsule Substances 0.000 description 13
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 12
- 108010006060 aviptadil Proteins 0.000 description 11
- 229950000586 aviptadil Drugs 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 9
- 239000007779 soft material Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000007903 gelatin capsule Substances 0.000 description 7
- 230000000750 progressive effect Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000002156 mixing Methods 0.000 description 6
- 238000004806 packaging method and process Methods 0.000 description 6
- 238000007873 sieving Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000000853 adhesive Substances 0.000 description 3
- 230000001070 adhesive effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- PPWLAQVKIFDULF-UHFFFAOYSA-N 2-phenyl-1h-pyrrolo[2,3-b]pyridine Chemical compound N1C2=NC=CC=C2C=C1C1=CC=CC=C1 PPWLAQVKIFDULF-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 125000005474 octanoate group Chemical group 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229960003056 phentolamine mesylate Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100037505 Secretin Human genes 0.000 description 1
- 108010086019 Secretin Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229960002101 secretin Drugs 0.000 description 1
- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Virology (AREA)
- Reproductive Health (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention discloses solid compositions comprising a vasoactive intestinal peptide and an absorption enhancer. The vasoactive intestinal peptide is avidinol, and the absorption enhancer is N- (8- (2-hydroxybenzoyl) amino) sodium octoate. The solid composition of the invention contains N- (8- (2-hydroxybenzoyl) amino) sodium octoate, can improve the bioavailability of the avidinol as an absorption enhancer, and has enhanced effect when being used together with a combined auxiliary agent.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a solid composition containing vasoactive intestinal peptide and an absorption enhancer.
Background
Aviptadil (Aviptadil) is a linear peptide containing 28 amino acids, and endogenous Aviptadil is also known as vasoactive intestinal peptide (Vasoactive interinal peptide, VIP). The amino acid sequence is shown as follows: his-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn.
The tripeptide is originally isolated from secretin in the small intestine of pigs, has a sequence somewhat similar to glucagon, and can increase vascular permeability, inhibit gastric acid secretion and gastric peristalsis, inhibit the action of smooth muscle contraction of the digestive tract in clinical manifestations, and is mainly used for treating acute respiratory distress syndrome and idiopathic pulmonary fibrosis, and is used as neurotransmitter or neuromodulator in a plurality of organs and tissues including heart, thyroid, kidney, urethra and reproductive organs. And has a certain effect on treating Pulmonary Arterial Hypertension (PAH).
Currently, alpidil has been used by intravenous administration or inhalation in controlled different human clinical trials. Meanwhile, the compound injection of the alpeptiddil and the phentolamine mesylate is also commercially available at present and is used for treating erectile dysfunction. Commercially available in Germany, norway, etc., under the trade name Invicorp ® Specification 25 μg/2mg (i.e., 25 μg of alpidide and 2mg of phentolamine mesylate per ampoule). The injection has the advantages of unchanged use, injection pain, easy occurrence of safety problems, and the like.
Disclosure of Invention
The object of the present invention is to provide a solid composition comprising a vasoactive intestinal peptide and an absorption enhancer.
A solid composition comprising a vasoactive intestinal peptide and an absorption enhancer, comprising vasoactive intestinal peptide, sodium N- (8- (2-hydroxybenzoyl) amino) caprylate (SNAC) and a combination aid.
The vasoactive intestinal peptide is avidiner.
The combined auxiliary agent is one or more of a filler, an adhesive, a disintegrating agent and a lubricant.
The filler is one or more of corn starch, pregelatinized starch, microcrystalline cellulose, lactose, dextrin, sucrose, mannitol and calcium sulfate dihydrate.
The adhesive is one or more of distilled water, methyl cellulose, ethyl cellulose, hypromellose, povidone, gelatin, polyethylene glycol, low-substituted hyprolose and sodium alginate.
The disintegrating agent is one or more of dry starch, carboxymethyl starch sodium, crosslinked povidone and crosslinked sodium carboxymethyl cellulose.
The lubricant is one or more of silicon dioxide, colloidal silicon dioxide, magnesium stearate, talcum powder and sodium stearyl fumarate.
The use of said solid composition comprising a vasoactive intestinal peptide and an absorption enhancer for the preparation of a medicament for the treatment of a disease.
The diseases include: acute respiratory distress syndrome, idiopathic pulmonary fibrosis to treat lung injury, acute lung injury, novel coronaviruses, adult male erectile dysfunction.
The solid composition is a capsule, adopts a preparation method of wet granulation, wets the surfaces of medicine powder by means of a liquid adhesive to generate certain adhesion force among the medicine powder, then forms particles with certain shape and size under the action of external force, finally is dried by drying equipment and is solidified in the form of solid particles to form particles, and the particles prepared by the wet granulation process have uniform appearance and good wear resistance.
The invention has the beneficial effects that: the solid composition of the invention contains N- (8- (2-hydroxybenzoyl) amino) sodium octoate, can improve the bioavailability of the avidinol as an absorption enhancer, and has enhanced effect when being used together with a combined auxiliary agent.
Detailed Description
The present invention will be described more fully hereinafter in order to facilitate an understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Example 1
An alpidil capsule comprises the following substances:
the preparation method comprises the following steps: sieving alpidil, lactose and croscarmellose sodium with 30 mesh sieve respectively for use; the prescription amount of the aviptadil, lactose and the croscarmellose sodium are uniformly mixed in an equal progressive manner, and a proper amount of povidone aqueous solution is used for preparing soft materials and finishing grains; drying and granulating the prepared granules; mixing the obtained granule with magnesium stearate, filling into size 2 gelatin capsule shell, and packaging.
Example 2
An alpidil capsule comprises the following substances:
the preparation method comprises the following steps: sieving alpidil, lactose, croscarmellose sodium and SNAC with 30 mesh sieve respectively for use; the prescription amount of the aviptadil, lactose, croscarmellose sodium and SNAC are uniformly mixed in an equal progressive mode, and a proper amount of povidone aqueous solution is used for preparing a soft material and finishing grains; drying and granulating the prepared granules; mixing the obtained granule with magnesium stearate, filling into size 2 gelatin capsule shell, and packaging.
Example 3
An alpidil capsule comprises the following substances:
the preparation method comprises the following steps: sieving alpidil, lactose, croscarmellose sodium and SNAC with 30 mesh sieve respectively for use; the prescription amount of the aviptadil, lactose, croscarmellose sodium and SNAC are uniformly mixed in an equal progressive mode, and a proper amount of povidone aqueous solution is used for preparing a soft material and finishing grains; drying and granulating the prepared granules; mixing the obtained granule with magnesium stearate, filling into size 2 gelatin capsule shell, and packaging.
Example 4
An alpidil capsule comprises the following substances:
the preparation method comprises the following steps: sieving alpidil, lactose, croscarmellose sodium and SNAC with 30 mesh sieve respectively for use; the prescription amount of the aviptadil, lactose, croscarmellose sodium and SNAC are uniformly mixed in an equal progressive mode, and a proper amount of povidone aqueous solution is used for preparing a soft material and finishing grains; drying and granulating the prepared granules; mixing the obtained granule with magnesium stearate, filling into size 2 gelatin capsule shell, and packaging.
Example 5
An alpidil capsule comprises the following substances:
the preparation method comprises the following steps: sieving alpidil, lactose, croscarmellose sodium and SNAC with 30 mesh sieve respectively for use; the prescription amount of the aviptadil, lactose, croscarmellose sodium and SNAC are uniformly mixed in an equal progressive mode, and a proper amount of povidone aqueous solution is used for preparing a soft material and finishing grains; drying and granulating the prepared granules; mixing the obtained granule with magnesium stearate, filling into size 2 gelatin capsule shell, and packaging.
Comparative example 1
An alpidil capsule comprises the following substances:
the preparation method comprises the following steps: screening SNACs with 30 meshes respectively for standby; the prescription amount of the aviptadil and the SNAC are uniformly mixed in an equal progressive mode, a proper amount of aqueous solution is used for preparing soft materials, and the soft materials are granulated; the prepared granules are dried, granulated and filled into a size 2 gelatin capsule shell, and then the granules are packaged.
Comparative example 2
An alpidil capsule comprises the following substances:
the preparation method comprises the following steps: sieving alpidil, lactose and croscarmellose sodium with 30 mesh sieve respectively for use; the prescription amount of the aviptadil, lactose and the croscarmellose sodium are uniformly mixed in an equal progressive manner, and a proper amount of povidone aqueous solution is used for preparing soft materials and finishing grains; drying and granulating the prepared granules; mixing the obtained granule with magnesium stearate, filling into size 2 gelatin capsule shell, and packaging.
Experimental example:
the aim of this study was to evaluate the oral bioavailability in rats of a series of solid compositions comprising alpeptiddil and SNAC. The capsule samples of examples 1 to 5 and comparative examples 1 to 2 were used.
Animals, dosing and blood sampling: male rats were used in the study, and the weight was 180-250 g during the study period. The administration is carried out by single oral administration in the fasting state. Blood samples were collected at the following time points: pre-dose, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24 hours post-dose.
Analysis of solid composition: the amount of alpeptiddil in the oral capsules was analyzed by LC-MS method, and the mobile phase gradient (solvent a: 0.1% aqueous formic acid; solvent B: 0.1% formic acid, 50% acetonitrile) was equilibrated with 100% solvent a for 1 min, starting with a linear rise to 100% B within 15 min.
Results: table 1 summarizes the pharmacokinetic parameters of the alpidil after single administration of the capsules shown in examples 1-5 and comparative examples 1-2.
Table 1: pharmacokinetic parameter summary
Conclusion: in this study, the capsules containing sodium N- (8- (2-hydroxybenzoyl) amino) octoate showed improved bioavailability compared to the capsules without sodium N- (8- (2-hydroxybenzoyl) amino) octoate, and the combined use of sodium N- (8- (2-hydroxybenzoyl) amino) octoate and a combination aid was synergistic.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (9)
1. A solid composition comprising a vasoactive intestinal peptide and an absorption enhancer, characterized in that it comprises vasoactive intestinal peptide, sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and a combination aid.
2. The solid composition comprising a vasoactive intestinal peptide and an absorption enhancer of claim 1, wherein the vasoactive intestinal peptide is alpidil.
3. The solid composition comprising a vasoactive intestinal peptide and an absorption enhancer of claim 1, wherein the combination aid is one or more of a filler, a binder, a disintegrant, and a lubricant.
4. The solid composition comprising a vasoactive intestinal peptide and an absorption enhancer of claim 3, wherein the filler is one or more of corn starch, pregelatinized starch, microcrystalline cellulose, lactose, dextrin, sucrose, mannitol, calcium sulfate dihydrate.
5. The solid composition comprising a vasoactive intestinal peptide and an absorption enhancer of claim 3, wherein the binder is one or more of distilled water, methyl cellulose, ethyl cellulose, hypromellose, povidone, gelatin, polyethylene glycol, low substituted hyprolose, sodium alginate.
6. A solid composition comprising a vasoactive intestinal peptide and an absorption enhancer according to claim 3, wherein the disintegrant is one or more of dry starch, sodium carboxymethyl starch, crospovidone, croscarmellose sodium.
7. A solid composition comprising a vasoactive intestinal peptide and an absorption enhancer according to claim 3, wherein the lubricant is one or more of silica, colloidal silica, magnesium stearate, talc, sodium stearyl fumarate.
8. Use of a solid composition comprising a vasoactive intestinal peptide and an absorption enhancer according to claim 1 for the manufacture of a medicament for the treatment of a disease.
9. Use of a solid composition comprising a vasoactive intestinal peptide and an absorption enhancer according to claim 8 for the manufacture of a medicament for the treatment of a disease comprising: acute respiratory distress syndrome, idiopathic pulmonary fibrosis to treat lung injury, acute lung injury, novel coronaviruses, adult male erectile dysfunction.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015104596A1 (en) * | 2014-01-10 | 2015-07-16 | Ipp Dr Hayley | Vasoactive intestinal peptide |
| CN114173766A (en) * | 2019-08-07 | 2022-03-11 | 诺和诺德股份有限公司 | Solid compositions comprising a GLP-1 agonist, an SGLT2 inhibitor, and a salt of N- (8- (2-hydroxybenzoyl) amino) caprylic acid |
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- 2023-06-01 CN CN202310635587.2A patent/CN116370609B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015104596A1 (en) * | 2014-01-10 | 2015-07-16 | Ipp Dr Hayley | Vasoactive intestinal peptide |
| CN114173766A (en) * | 2019-08-07 | 2022-03-11 | 诺和诺德股份有限公司 | Solid compositions comprising a GLP-1 agonist, an SGLT2 inhibitor, and a salt of N- (8- (2-hydroxybenzoyl) amino) caprylic acid |
Non-Patent Citations (2)
| Title |
|---|
| JIHAD GEORGES YOUSSEF等: "The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID- 19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial", CRITICAL CARE MEDICINE, pages 1545 - 1554 * |
| LEI WANG等: "Therapeutic peptides: current applications and future directions", SIGNAL TRANSDUCTION AND TARGETED THERAPY, vol. 7, pages 1 - 27 * |
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